Matrix Rigidity Regulates Cancer Cell Growth by Modulating Cellular Metabolism and Protein Synthesis 英文参考文献.docVIP

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Matrix Rigidity Regulates Cancer Cell Growth by Modulating Cellular Metabolism and Protein Synthesis 英文参考文献.doc

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Matrix Rigidity Regulates Cancer Cell Growth by Modulating Cellular Metabolism and Protein Synthesis 英文参考文献

MatrixRigidityRegulatesCancerCellGrowthby ModulatingCellularMetabolismandProteinSynthesis RobertW.Tilghman1*,EdikM.Blais2,CatharineR.Cowan1,NicholasE.Sherman1,PabloR.Grigera1, ErinD.Jeffery1,JayW.Fox1,BrettR.Blackman2,DanielJ.Tschumperlin3,JasonA.Papin2 ,J. ThomasParsons1 1Department ofMicrobiology, ImmunologyandCancerBiology,UniversityofVirginia,Charlottesville,Virginia,United StatesofAmerica, 2Department ofBiomedical Engineering,UniversityofVirginia,Charlottesville,Virginia,UnitedStatesofAmerica,3MolecularandIntegrativePhysiologicalSciences,HarvardSchoolofPublicHealth, Boston,Massachusetts,UnitedStatesofAmerica Abstract Background:Tumorcellsinvivoencounterdiversetypesofmicroenvironmentsbothatthesiteoftheprimarytumorandat sitesofdistantmetastases.Understandinghowthevariousmechanicalpropertiesofthesemicroenvironmentsaffectthe biologyoftumorcellsduringdiseaseprogressioniscriticalinidentifyingmoleculartargetsforcancertherapy. Methodology/PrincipalFindings:Thisstudyusesflexiblepolyacrylamidegelsassubstratesforcellgrowthinconjunction withanovelproteomicapproachtoidentifythepropertiesofrigidity-dependentcancercelllinesthatcontributetotheir differentialgrowthonsoftandrigidsubstrates.Comparedtocellsgrowingonmorerigid/stiffsubstrates(.10,000Pa),cells onsoftsubstrates(150–300Pa)exhibitedalongercellcycle,duepredominantlytoanextensionoftheG1phaseofthecell cycle,andweremetabolicallylessactive,showingdecreasedlevelsofintracellularATPandamarkedreductioninprotein synthesis.Usingstableisotopelabelingofaminoacidsinculture(SILAC)andmassspectrometry,wemeasuredtheratesof protein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identified cellularproteinswhosesyntheseswereeitherpreferentiallyinhibitedorpreservedonsoftmatrices.Theformercategory includedproteinsthatregulatecytoskeletalstructures(e.g.,tubulins)andglycolysis(e.g.,phosphofructokinase-1),whereas the latter category included proteins that regulate key metabolic pat